Acute lymphoblastic leukemias that bear chromosomal translocations at 11q23 possess rearrangements of the Mixed Lineage Leukemia gene (MLL, HRX, ALL-1) and have a poor prognosis. Both i n f a nt leukemia and secondary leukemias following therapy with DNA topoisomerase II inhibitors frequently bear MLL translocations. This project will utilize genetic models and RNA profiling to determine the function and the critical target genes of Mll. A series of selected loss-of-function models of Mll in distinct hematopoietic lineages will reveal the normal roles of Mll, enable the profiling of Hox expression and discover additional targets using DNA microarray technology. The gene expression program controlled by Mll in murine hematopoietic cells will then be compared to the program of gene expression in Mll-fusion containing hematopoietic cells and murine Mll- dependent leukemia. In collaboration with Todd Golub, we will determine the expression profile of poor prognosis MLL-dependent human leukemia as it compares to that of more favorable prognosis leukemia. Comparison of the expression profiles from human and murine leukemia with that of Mll null hematopoietic lineages should help direct us to the genes regulated by Mll that are important in leukemogenesis.